research

gastrointestinal research in inflammation & pathology (GRIP)

summary

This research group are interested in understanding the mechanisms underlying chronic inflammatory diseases of the gut like inflammatory bowel disease , gastric cancer and eosinophilic oesophagitis. Inflammatory bowel diseases, particularly Crohn's disease, increasingly afflicts children, while Helicobacter pylori, the bug that causes stomach ulcers and cancer, infects half the world's population, often beginning in childhood. Both these diseases occur when there is uncontrolled inflammation. Our aim is to understand why this occurs, the nature of the inflammatory response, and how we can intervene to prevent it.

group leader(s)

Professor Andy GiraudAndy Giraud
Murdoch Childrens Research Institute
Royal Children's Hospital
Flemington Road
Parkville Victoria 3052

T +61 3 8341 6446
E andrew.giraud@mcri.edu.au

group leader biography

 

 

 

 

 

Dr Louise Judd
Murdoch Childrens Research Institute
Royal Children's Hospital
Flemington Road
Parkville Victoria 3052

E louise.judd@mcri.edu.au

current research projects

Project 1: New mouse models of Crohn's disease

We are carrying out forward genetic screens in mice (ENU mutagenesis) to produce and characterise new models of inflammatory bowel diseases, particularly those modelling Crohn's disease. This cutting edge technology produces targeted mutations closely mimicking changes seen in human disease. Currently we have several promising new models under development and are screening for others. We hope to use these models to better understand susceptibility genes in Crohn's development and for testing new therapeutics.

Project 2: Chronic cytokine drive of cancers of the upper gut

Stomach cancer is the second most common cause of cancer death worldwide, with most cases occurring in South East Asia. Disease occurs in response to continuous inflammation over many years, in response to H. pylori infection starting in childhood in susceptible individuals. We have characterised a mouse model of the disease which closely mirrors the development of the most common intestinal-type stomach adenocarcinoma in humans. We have shown that the cytokine IL-11 is crucial for cancer growth  and that it's target transcription factor STAT3, when continuously activated, causes cancer. We have successfully confirmed that the major findings from the mouse model (high cytokine drive, ongoing STAT3 activation, and a unique tumour-associated macrophage profile) also occur in precancerous and cancerous lesions in humans. We are now trialling novel STAT3 inhibitors in preclinical testing for their ability to prevent or inhibit stomach tumour growth.

Project 3: Identification of novel anti-cancer and repair-modifying genes in the gut

The gastrokine 2 (GKN2) gene product acts as a binding protein for trefoil factor 1, which functions as a stomach-specific anti-cancer (tumour suppressor) gene and local regulator of tissue repair. We have recently shown that GKN2 may also act independently to prevent stomach cancer, since it is strongly inhibited in the gastric cancer mouse and in human cancer cell lines. Recently we have knocked out the GKN2 gene by homologous recombination and are analysing its phenotype. Current research is aimed at understanding GKN2 function in preventing tumour growth and in facilitating repair processes, as well as in developing therapeutics to turn up GKN2 activity or prevent its inhibition prior to tumour development.

Project 4: Epigenetic silencing of gstric tumour suppressor gene by bacterial inflammation

The capacity of the immune system to regulate the epigenetic modification of DNA has major implications for human health, but remains unexplored as a strategy for disease therapy. Gastric cancer has a very high mortality rate and is caused by chronic inflammation arising from infection with the bacterium Helicobacter pylori (H. pylori). We have recently established a novel link between chronic inflammation caused by H. pylori and the epigenetic inactivation or 'silencing' of a stomach-specific tumour suppressor gene, trefoil factor (TFF)2. We are currently investigating the origin and functional impact of TFF2 and other inflammation-related epigenetic signatures using mouse models of H. pylori-dependent and independent gastric inflammation, preneoplasia and tumourigenesis, as well as genetic models of immune and cytokine receptor deficiency. The outcomes of this project are anticipated to have broad application in inflammatory disorders of the gastrointestinal tract such as inflammatory bowel disease (IBD), as well as in widespread adult cancers such as colorectal cancer.

team members

  • Jon Buzzelli - PhD Student (UoM Paeds)
  • Heather Chalinor - Research Assistant
  • Sharon Clohesy - Personal Assistant
  • Shelley Jacobs - Research Assistant
  • Bayzar Kurklu - PhD Student (UoM Paeds)
  • Trevelyan Menheniott - Senior Research Officer
  • Maria Nguyen - BMedSci(Hons) (Monash MIMR-RitchieCntr)
  • Louise O'Connor - Research Assistant
  • Dan Pavlic - Honours Student (UoM Paeds)
  • Bob Whitehead - HONORARY RESEARCH FELLOW
  • Daniel Worthley - Postdoctoral Research Fellow

publications

  • Chaiyarit P., Chayasadom A., Wara-aswapati N., Hormdee D., Sittisomwong S., Nakaresisoon S., Samson MH., Pitiphat W., Giraud AS. Trefoil Factors in Saliva and Gingival Tissues of Patients With Chronic Periodontitis. Journal of Periodontology (2011) PubMed
  • Chaiyarit P., Utrawichian A., Leelayuwat C., Vatanasapt P., Chanchareonsook N., Samson MH., Giraud AS. Investigation of trefoil factor expression in saliva and oral mucosal tissues of patients with oral squamous cell carcinoma. Clinical Oral Investigations (2011) PubMed
  • KAMLUA S., PATRAKITOMJORN S., JEARANAIKOON P., MENHENIOTT TR., GIRAUD AS., LIMPAIBOON T. Alternative splicing isoforms of TFF2 (?EX2TFF2) mRNA in cholangiocarcinoma. Oncology Reports  (2011) PubMed
  • Kosriwong K., Menheniott TR., Giraud AS., Jearanaikoon P., Sripa B., Limpaiboon T. Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma. WORLD JOURNAL OF GASTROENTEROLOGY 17 (12) : 1631 - 1641(2011) PubMed
  • Meegan Howlett., Heather V Chalinor., Jon N Buzzelli., Nhung Nguyen., Ian R van Driel., Katrina M Bell., James G Fox., Eva Dimitriadis., Trevelyan R Menheniott., Andrew S Giraud., Louise M Judd. IL-11 is a parietal cell cytokine that induces atrophic gastritis. Gut (2011) PubMed
  • Mercer S., Mutton P., Dahl HHM. Identification of SLC26A4 Mutations in Patients with Hearing Loss and Enlarged Vestibular Aqueduct Using High-Resolution Melting Curve Analysis. GENETIC TESTING AND MOLECULAR BIOMARKERS 15 (5) : 365 - 368(2011) PubMed
  • Nhung N., Judd LM., Kalantzis A., Whittle B., Giraud AS., van Driel IR. Random mutagenesis of the mouse genome: a strategy for discovering gene function and the molecular basis of disease. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 300 (1) (2011) PubMed
  • Nieminen P., Morgan NV., Fenwick AL., Parmanen S., Veistinen L., Mikkola ML., van der Spek PJ., Giraud A., Judd L., Arte S., Brueton LA., Wall SA., Mathijssen IMJ., Maher ER., Wilkie AOM., Kreiborg S., Thesleff I. Inactivation of IL11 Signaling Causes Craniosynostosis, Delayed Tooth Eruption, and Supernumerary Teeth. American Journal of Human Genetics 89 (1) : 67 - 81(2011) PubMed

competitive funding

National Health & Medical Research Council
ARC

collaborations & affiliations

Tim Wang, Columbia University, USA
Jim Fox, MIT, USA
Masanobu and Hiroko Oshima, Kanazawa, Japan
Masanori Hatakeyama, Tokyo, Japan
Ian van Driel, Bio21, Australia